Studies On The Antitumor Effect Of Oleanolic Acid On Human Pancreatic Cancer Cells

Pancreatic cancer is one of the most common malignant tumors in man. Despiteadvances in surgical and non-surgical treatments, it remains a big challenge duo to itspoor prognosis; an overall5-year survival rate is only3-5%due to the lack ofsymptoms and screening techniques for early detection, aggressive metastaticbehavior, and resistance to conventional chemotherapy and radiotherapy regimens.Therefore, there is an urgent need to develop novel agents and alternative strategiesfor the treatment of pancreatic cancer.Oleanolic acid (OA), a pentacyclic triterpenoid, exhibits potential anti-tumoractivity against many tumor cell lines. Due to its marked antitumor effects andpharmacological safety, the antitumor activity of OA has attracted more attention.However, little is known about the underlining mechanism of OA induced anticanceractivity. In the present study, we study the anti-tumor activity of OA on pancreaticcancer cells and its potential molecular mechanism. The results showed that theproliferation of Panc-28cells was inhibited by OA in a concentration-dependentmanner, with an IC50value of46.35g ml-1, as determined by MTT assay. The cellcycle was arrested in S phase and G2/M phase by OA. The study also showed that OAcould induce remarkable apoptosis, evidenced by increased percentage of early/lateapoptotic cells, DNA ladder and nuclear morphology change. Further study revealedthat OA could induce apoptosis possibly via ROS-mediated mitochondrial andlysosomal pathway in Panc-28cells. Secondly, the study investigates the effects of theoleanolic acid on the proliferation,migration and the formation of tube-like structurein human vascular endothelial cells (HUVECs). MTT assay showed that the inhibitionrates of HUVECs treated with60and80g ml-1of oleanolic acid for24h were11.22%and41.88%respectively. Treatment of HUVECs significantly inhibited the cell migration in a dose-dependent manner. The vascular index of HUVECs treatedwith40and60g ml-1were33%and20%respectively. Western blot analysis showedthat treatment of the cells with oleanolic acid significantly attenuated the expressionand secretion of VEGF. Thirdly, the combination of OA and5-FU on the humanpancreatic Panc-28cells was studied. The results showed the combined use of OA and5-FU synergistically potentiated cell death effects on Panc-28cells, and the apoptoticeffect was also increased. Further study revealed that the combined treatment couldenhance mitochondrial depolarization, lysosomal membrane permeabilization (LMP)and leakage of cathepin D, while the release of cytochrome C did not displaysignificant changes. The expression of apoptosis related proteins was also affected incells treated with the combination of OA and5-FU, including activation of caspases-3and the expression of Bcl-2/Bax, Survivin. The result also showed that OAdid notaffect the expression of p53, and the level of NF-κB was upregulated.In conclusion, OA can inhibit tumor growth and development through a varietyof tagarts, and the use of combination with5-FU can display synergistic anti-tumoreffect. OA has a potential to become a novel agent and alternative strategy for thetreatment of pancreatic cancer.